Sch527123 [2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide] is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al., 2007). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, as well as its in vivo activity in models demonstrating prominent pulmonary neutrophilia, goblet cell hyperplasia, and mucus production. Sch527123 bound with high affinity to the CXCR2 receptors of mouse (K d ϭ 0.20 nM), rat (K d ϭ 0.20 nM), and cynomolgus monkey (K d ϭ 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC 50 ϳ3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K d ϭ 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC 50 ϳ1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED 50 ϭ 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED 50 ϭ 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED 50 ϭ Ͻ0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED 50 ϭ 1.3 mg/kg), goblet cell hyperplasia (ED 50 ϭ 0.7 mg/kg), and increase in BAL mucin content (ED 50 ϭ Ͻ1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduced the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED 50 ϭ 0.3 mg/kg). Therefore, Sch527123 may offer benefit for the treatment of inflammatory lung disorders in which pulmonary neutrophilia and mucus hypersecretion are important components of the underlying disease pathology.Chronic obstructive pulmonary disease (COPD) is the fourth major cause of death in the United States and is characterized by irreversible airflow limitation due to chronic bronchitis or emphysema (Barnes and Stockley, 2005). The pathological hallmarks of COPD include peripheral airway inflammation dominated by neutrophils, the destruction of the lung parenchyma, submucosal gland hypertrophy, and goblet cell hyperplasia, as well as an increase in proinflammatory cytokines and chemokines (Barnes and Stockley, 2005). Current therapies for COPD are similar to those for asthma and include the use of -adrenoceptor agonists, theophylline, muscarinic antagonists, and corticosteroids (Barnes and Stockley, 2005). However, these treatments do not prevent the progressive decline in lung function and demonstrate clinical activity in only a subpopulation of COPD patients. There is a strong correlation between disease Article, publication date, and citation information can be found at